Introduction to Experimental Toxicology

D. M. CONNING

Toxicology is defined, classically, as the study of the adverse effects of chemicals on living systems. Originally this meant the study of poisons and that meaning remains the most satisfactory of definitions, essentially because it embodies the concept of the effect being proportional to the administered dose. Although the popular concept of poison concerns poisoning to death, the true study of poisons embraces the induction of morbid changes that are not necessarily fatal.

In this sense, the study of toxicology came to be regarded as an extension of the study of pharmacology and it is still so regarded by those who take a pedantic view of the topic. Of necessity, a pharmacological assay must explore the optimum dose in relation to the maximum therapeutic effect, and thus the dosage at which the effect is counter-productive of the desired result. In many ways the association of pharmacology and toxicology has been beneficial to the latter as a burgeoning science because it instilled two basic constraints which reinforced the scientific nature of the study. First was the recognition that pharmacology involved the perturbation of physiological function. That is, it was realised that a variety of detectable changes were compatible with normal living, and pharmacology sought to enhance those aspects which would be beneficial in the presence of disease or inhibit others for the same purpose. Second, the pharmacological study was a study of a defined function such as heart function, nerve transmission, or renal reabsorption, and never involved a less specific or more abstruse objective such as that embodied in the question 'Do any effects occur?' In other words, the pharmacological approach demanded an investigation of the way a particular physiological function could be chemically modified.

In recent decades, the definition of toxicology has been expanded in a way which has taken it firmly and, it seems, irrevocably out of the field of pharmacology. The first and most fundamental change was to add another purpose to the study. Thus toxicology came to be defined as the study of the adverse effects of chemicals on living systems in order to predict chemical hazard to man. This had the effect of classifying toxicology as an ancillary to public or community health, and by extension to preventive medicine, always the poor brother of therapeutic medicine; and at the same time imposed impossible conditions on its practice as a science. Not only did the study of toxicology become a study of the effects of a chemical on any conceivable physiological function, defined or not, but under any conceivable circumstances because of the almost infinite variety of human activity and behaviour. Toxicology was expected thereby to predict the effect of a chemical in systems which themselves were not capable of being defined.

The problem was compounded by a further expansion of the definition to include 'chemicals or other agents' and the inclusion of 'man or his environment.' Thus toxicology is the study of the adverse effects of chemicals or other agents on living systems in order to predict hazard to man and his environment.

A number of very unsatisfactory consequences have resulted from these developments. The first was the birth of the concept of the 'no-effect level' and its embodiment in safety regulations. It is simply not possible at the present stage of development of toxicological knowledge to define with any precision the normal values for many biological activities and thus to define when abnormal values are detected. The best we can do is to define where the values in treated systems (e.g. the experimental rat) differ from those in untreated systems maintained in similar circumstances. We know only rarely whether any observed differences represent a toxic effect or an adaptive response. Sometimes we have great difficulty in determining if there are any differences at all, a problem which has given rise to a massive development in biometrics.

Our adherence to the 'no-effect level' has undermined our faith in epidemiology. Although the lack of epidemiological data and the relative insensitivity of epidemiological methods have themselves contributed to this outcome, it has seemed easier to put our faith in animal results which can be determined with some precision and therefore appear to be more easily judged. The result is that attempts to extrapolate the findings in animals, for example, to predictable effects in man have no basis in human experience and tend to assume that man's response will be the same as that of the animal.

Another consequence has been distortion of the economics of toxicological practice in that those who are involved with toxicological experiment spend so much of their time and resources generating data, there is very little available for scientific interpretation and further experiment. The construction and testing of hypotheses do not have a prominent role in toxicology.

All of this has come about for the best possible motives. The perception of the possible dangers consequent upon our chemical inventiveness has resulted in the appearance of potent forces to protect human communities against such consequences. The diligent pursuit of detail...